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A porcine model of osteosarcoma

We previously produced pigs with a latent oncogenic TP53 mutation. Humans with TP53 germline mutations are predisposed to a wide spectrum of early-onset cancers, predominantly breast, brain, adrenal gland cancer, soft tissue sarcomas and osteosarcomas. Loss of p53 function has been observed in >5...

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Autores principales: Saalfrank, A, Janssen, K-P, Ravon, M, Flisikowski, K, Eser, S, Steiger, K, Flisikowska, T, Müller-Fliedner, P, Schulze, É, Brönner, C, Gnann, A, Kappe, E, Böhm, B, Schade, B, Certa, U, Saur, D, Esposito, I, Kind, A, Schnieke, A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815050/
https://www.ncbi.nlm.nih.gov/pubmed/26974205
http://dx.doi.org/10.1038/oncsis.2016.19
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author Saalfrank, A
Janssen, K-P
Ravon, M
Flisikowski, K
Eser, S
Steiger, K
Flisikowska, T
Müller-Fliedner, P
Schulze, É
Brönner, C
Gnann, A
Kappe, E
Böhm, B
Schade, B
Certa, U
Saur, D
Esposito, I
Kind, A
Schnieke, A
author_facet Saalfrank, A
Janssen, K-P
Ravon, M
Flisikowski, K
Eser, S
Steiger, K
Flisikowska, T
Müller-Fliedner, P
Schulze, É
Brönner, C
Gnann, A
Kappe, E
Böhm, B
Schade, B
Certa, U
Saur, D
Esposito, I
Kind, A
Schnieke, A
author_sort Saalfrank, A
collection PubMed
description We previously produced pigs with a latent oncogenic TP53 mutation. Humans with TP53 germline mutations are predisposed to a wide spectrum of early-onset cancers, predominantly breast, brain, adrenal gland cancer, soft tissue sarcomas and osteosarcomas. Loss of p53 function has been observed in >50% of human cancers. Here we demonstrate that porcine mesenchymal stem cells (MSCs) convert to a transformed phenotype after activation of latent oncogenic TP53(R167H) and KRAS(G12D), and overexpression of MYC promotes tumorigenesis. The process mimics key molecular aspects of human sarcomagenesis. Transformed porcine MSCs exhibit genomic instability, with complex karyotypes, and develop into sarcomas on transplantation into immune-deficient mice. In pigs, heterozygous knockout of TP53 was sufficient for spontaneous osteosarcoma development in older animals, whereas homozygous TP53 knockout resulted in multiple large osteosarcomas in 7–8-month-old animals. This is the first report that engineered mutation of an endogenous tumour-suppressor gene leads to invasive cancer in pigs. Unlike in Trp53 mutant mice, osteosarcoma developed in the long bones and skull, closely recapitulating the human disease. These animals thus promise a model for juvenile osteosarcoma, a relatively uncommon but devastating disease.
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spelling pubmed-48150502016-07-15 A porcine model of osteosarcoma Saalfrank, A Janssen, K-P Ravon, M Flisikowski, K Eser, S Steiger, K Flisikowska, T Müller-Fliedner, P Schulze, É Brönner, C Gnann, A Kappe, E Böhm, B Schade, B Certa, U Saur, D Esposito, I Kind, A Schnieke, A Oncogenesis Original Article We previously produced pigs with a latent oncogenic TP53 mutation. Humans with TP53 germline mutations are predisposed to a wide spectrum of early-onset cancers, predominantly breast, brain, adrenal gland cancer, soft tissue sarcomas and osteosarcomas. Loss of p53 function has been observed in >50% of human cancers. Here we demonstrate that porcine mesenchymal stem cells (MSCs) convert to a transformed phenotype after activation of latent oncogenic TP53(R167H) and KRAS(G12D), and overexpression of MYC promotes tumorigenesis. The process mimics key molecular aspects of human sarcomagenesis. Transformed porcine MSCs exhibit genomic instability, with complex karyotypes, and develop into sarcomas on transplantation into immune-deficient mice. In pigs, heterozygous knockout of TP53 was sufficient for spontaneous osteosarcoma development in older animals, whereas homozygous TP53 knockout resulted in multiple large osteosarcomas in 7–8-month-old animals. This is the first report that engineered mutation of an endogenous tumour-suppressor gene leads to invasive cancer in pigs. Unlike in Trp53 mutant mice, osteosarcoma developed in the long bones and skull, closely recapitulating the human disease. These animals thus promise a model for juvenile osteosarcoma, a relatively uncommon but devastating disease. Nature Publishing Group 2016-03 2016-03-14 /pmc/articles/PMC4815050/ /pubmed/26974205 http://dx.doi.org/10.1038/oncsis.2016.19 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Saalfrank, A
Janssen, K-P
Ravon, M
Flisikowski, K
Eser, S
Steiger, K
Flisikowska, T
Müller-Fliedner, P
Schulze, É
Brönner, C
Gnann, A
Kappe, E
Böhm, B
Schade, B
Certa, U
Saur, D
Esposito, I
Kind, A
Schnieke, A
A porcine model of osteosarcoma
title A porcine model of osteosarcoma
title_full A porcine model of osteosarcoma
title_fullStr A porcine model of osteosarcoma
title_full_unstemmed A porcine model of osteosarcoma
title_short A porcine model of osteosarcoma
title_sort porcine model of osteosarcoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815050/
https://www.ncbi.nlm.nih.gov/pubmed/26974205
http://dx.doi.org/10.1038/oncsis.2016.19
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